title: Safety and pharmacokinetics of a recombinant fusion protein linking coagulation factor VIIa with albumin in healthy volunteers.
abstract: BACKGROUND
  Development of neutralizing antibodies remains the most problematic complication in treating congenital hemophilia. Control and prevention of bleeding events in such patients with recombinant factor VIIa (rFVIIa) is limited by the short half-life of the available product. Here, we report on the pharmacokinetics and safety of a novel, recombinant fusion protein linking coagulation FVIIa with albumin (rVIIa-FP) in a first-in-human study in healthy male subjects.
  
  
  METHODS
  Forty healthy male subjects between 18 and 35 years of age were included and dosed in five consecutive cohorts. In each cohort, six subjects were randomized to a single dose of rVIIa-FP (140, 300, 500, 750, or 1000 μg kg(-1) ) and two to placebo. All subjects received anticoagulation with an oral vitamin K antagonist to reach an international normalized ratio between 2 and 3 prior to dosing with rVIIa-FP/placebo. Dosing with oral vitamin K antagonist was continued at a fixed dose for 6 days after injection of rFVIIa.
  
  
  CONCLUSIONS
  Tolerance of rVIIa-FP was good at all dose levels. No serious adverse events were observed. None of the subjects developed anti-drug antibodies. The maximum baseline-corrected mean (SD) FVIIa plasma activity increased in a dose-proportional manner. Across the dose range, the median half-life was consistent, ranging from 6.1 to 9.7 h. At the highest dose of 1000 μg kg(-1) , the median FVIIa activity-based half-life was 8.5 h. Clearance ranged from 7.62 to 12.74 mL h(-1) kg(-1) . Compared with the commercially available rFVIIa product, rVIIa-FP had a reduced clearance resulting in an approximately 3- to 4-fold increase in half-life.
authors.affiliation: PAREXEL International GmbH, Berlin, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Golor
authors.forename: D
authors.initials: D
authors.lastname: Bensen-Kennedy
authors.forename: S
authors.initials: S
authors.lastname: Haffner
authors.forename: R
authors.initials: R
authors.lastname: Easton
authors.forename: K
authors.initials: K
authors.lastname: Jung
authors.forename: T
authors.initials: T
authors.lastname: Moises
authors.forename: J-P
authors.initials: JP
authors.lastname: Lawo
authors.forename: C
authors.initials: C
authors.lastname: Joch
authors.forename: A
authors.initials: A
authors.lastname: Veldman
mesh_terms: D000293:Adolescent; D000328:Adult; D000418:Albumins / Q000737:chemistry* / Q000493:pharmacokinetics; D057134:Antibodies, Neutralizing / Q000097:blood; D000991:Antithrombins / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015942:Factor VIIa / Q000737:chemistry* / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006470:Hemorrhage / Q000517:prevention & control; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D010314:Partial Thromboplastin Time; D061214:Patient Safety; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D013917:Thrombin / Q000737:chemistry; D016896:Treatment Outcome; D014812:Vitamin K / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D000418:Albumins; D057134:Antibodies, Neutralizing; D000991:Antithrombins; D011993:Recombinant Fusion Proteins; D014812:Vitamin K; D015942:Factor VIIa; D013917:Thrombin
keywords: factor VIIa; factor eight inhibitor bypassing activity; half-life; hemophilia A; hemophilia B